4-amidino chroman and 4-amidino pyrano (3,2-c) pyridine derivatives, a process for their preparation and pharmaceutical compositions containing them

ABSTRACT

The present invention deals with 4-amidino chroman and 4-amidino pyrano (3,2-c) pyridine derivatives, a process for their preparation and pharmaceutical compositions containing them. Said derivatives have antihypertensive and antiarythmic activities. They respond to formula ##STR1## in which: A+B=--CH═CH--CH═N-- ou --CH═CR 4  --CR 5  ═CH--; 
     X=N, N→O, C-Z; 
     R 1  =H, CN, NO 2 , C 1  -C 4  alkyl, OH, C 1  -C 4  alcoxy, CF 3  CO--, CH 3  --SO 2  --, 
     ρ--SO 2  --; 
     R 2  =H; 
     R 3  =OH ou OCOCH 3   
     ou R 2  +R 3  =double bond.

This application is a Division of application Ser. No. 07/606,864, filedOct. 31, 1990, now U.S. Pat. No. 5,116,849.

The object of the present invention is 4-amidino chroman and 4-amidinopyrano (3,2-c) pyridine derivatives, a process for their preparation andpharmaceutical compositions containing them. The said derivatives haveantihypertensive and antiarrhythmic activities.

The Belgian patent 829 611 mentions a whole series of derivatives of3-chromanol with antihypertensive activity; these derivatives arecharacterized by the presence at position 4 of a NR₁ R₂ group in whichR₁ is a hydrogen or an optionally substituted hydrocarbon group, R₂ ishydrogen or an alkyl, NR₁ R₂ being optionally a heterocyclic groupcontaining from 3 to 8 atoms, unsubstituted or substituted by one or twomethyl groups and by the optional presence of a large number of possiblesubstituents at position 6 or at position 7.

The European patent application No. 273 262 describes chromanderivatives of formula: ##STR2## in which in particular: R'₅ denotes aheterocyclic group such as 2-pyridon-1-yl, 2-pyridazinon-1-yl,2-pyrimidon-1-yl, 6-pyrimidon-1-yl, 2-pyrazinon-1-yl,2-thiopyridon-1-yl; this group being partially hydrated, substituted orunsubstituted;

R'₃ represents OH or OCOCH₃ ;

R'₄ represents hydrogen or else R'₃ and R'₄ together form a bond.

The European patent applications 296 975 and 312 432 describe similarcompounds.

Finally, the European patent application 205 292 describes pyrano[3,2-c] pyridine derivatives of formula: ##STR3## in which X" representsO or S and R"₅ and R"₆ may form a heterocycle.

Novel compounds, chroman and pyrano (3,2-c) pyridine derivatives, havenow been found which possess activity as antihypertensive andantiarrhythmic agents.

Thus, in respect to one of its features, the present invention relatesto compounds of formula: ##STR4## in which: A and B are linked togetherbetween N and C=NR₁ and represent

either a --CH═CH--CH═N-- group

or a --CH═CR₄ --CR₅ ═CH-- group, one of the substituents R₄ or R₅denoting hydrogen, the other being selected from hydrogen, halogen,nitro or C₁ -C₄ alkyl;

X represents a nitrogen atom, a N-oxide group or the C-Z group;

Z represents hydrogen, halogen, C₁ -C₄ alkyl, cyano, nitro, acetyl ortrifluoroacetyl, phosphono or dialkoxyphosphoryl in which the alkyl is aC₁ -C₃ group or an amino group;

R₁ represents hydrogen, cyano, nitro, C₁ -C₄ alkyl, hydroxyl, C₁ -C₄alkoxy, trifluoroacetyl, methanesulfonyl, benzenesulfonyl unsubstitutedor substituted on the phenyl by methyl, halogen or trifluoromethyl;

R₂ represents hydrogen;

R₃ represents hydroxyl or acetyloxy or R₂ and R₃ together form a bond.

In the present description and in the claims which follow, halogen meansa chlorine, bromine or fluorine atom.

The compounds of formula (I) in which R₂ =H and R₃ =OH or OCOCH₃ havethe trans configuration. They may contain two asymmetric carbon atoms.The present invention includes each of the optical isomers of thecompounds of formula (I) as well as the racemate.

Another object of the present invention is a process for the preparationof the compounds (I).

The said process is characterized in that:

a) an epoxide II of formula: ##STR5## in which X has the meanings givenabove in the case of I, is treated with a heterocycle III correspondingto one of the following tautomeric forms: ##STR6## in which A, B and R₁have the meanings previously indicated for (I); b) acetic anhydride isoptionally reacted with the compound obtained of formula (I) in which R₂=H and R₃ =OH in order to prepare the compound of formula (I) in whichR₂ =H and R₃ =--OCOCH₃ ;

c) the compound obtained in step a) of formula (I) in which R₂ =H and R₃=OH or the compound obtained in step b) of formula (I) in which R₂ =Hand R₃ =OCOCH₃ is optionally treated in order to prepare a compound offormula (I) in which R₂ and R₃ together form a bond.

In step (a), the epoxide (II) ring-opening reaction is conducted at atemperature between 10° C. and 100° C. in an inert organic solvent suchas dioxane, tetrahydrofuran, methyl-tert.-butyl ether, dimethylsulfoxideor dimethylformamide in the presence of a basic condensing agent such assodium hydride, triethylamine, a quarternary ammonium hydroxide such asbenzyltrimethylammonium hydroxide. Under such operating conditions, theopening of the epoxide (II) leads to compounds of formula (I) having thetrans configuration in which R₂ =H and R₃ =OH.

In step b), the acetylaton is performed at a temperature between 20° and100° C. for a period varying from 1 to 48 hours in a basic solvent suchas pyridine or triethylamine.

In step c), the dehydration of the compound prepared in step a) isobtained by reaction of an alkali hydride, for example sodium hydride orlithium hydride, in an inert solvent at a temperature between 20° C. and100° C.; the deacetylation of the compound prepared in step b) iseffected in the presence of diazabicycloundecene by heating between 50°and 110° C. in an inert solvent such as toluene or benzene.

The epoxides of formula (II) are known or prepared according to knownmethods.

The epoxide (II) in which X represents a nitrogen atom is described inthe European patent application 205 292. The epoxide (II) in which Xrepresents a N-oxide group is described in the application WO 89/10925.The epoxides (II) in which X represents the C-Z group are described invarious publications.

Thus, the epoxide (II) in which Z represents the cyano group isdescribed in the Belgian patent 852 955; the epoxide (II) in which Zrepresents the nitro group or an acetyl group is described in J. Med.Chem., 1983, 23, 1582-1589; the epoxides (II) in which Z represents ahalogen are prepared according to Tetrahedron, 1981, 37 (15), 2613-2616.The epoxides (II) in which Z represents the trifluoroacetyl or aphosphono group or a dialkoxyphosphoryl group in which the alkyl is C₁-C₃ are described in the European patent application 296 975. Theepoxide (II) in which Z represents hydrogen is described in J. Chem.Soc., 1962, 76-79. The epoxide (II) in which Z is a methyl is describedin Aust. J. Chem. 1979, 32 (3), 619-636; when Z represents a C₂ -C₄alkyl, the epoxide (II) is obtained in an analogous manner. Finally, theepoxide (II) in which Z represents a NH₂ group is described in theEuropean patent application 273 262 . It may also be obtained byreduction of the epoxide (II) in which Z represents NO₂.

The heterocyclic compounds (III) are known or prepared by known methods.In particular, in the case of the preparation of the cyanamino pyridinesor pyrimidines, the method described in Ann. Pharm. Fr., 1968, 26 (6),469-472 may be used. The sulfonamino pyridines are described in DokladyAka. Nauk. S.S.S.R., 1957, 113, 1080-3. They may be prepared by reactionof the appropriate sulfonyl derivative on the aminopyridine. Moreover,standard methods of organic chemistry have been applied to thepreparation of some compounds (III). Thus, the compounds (III) in whichR₁ is a nitro group are used to prepare the compounds (III) in which R₁is a C₁ -C₄ alkyl by reaction with a C₁ -C₄ alkylamine in basic medium.Said compounds (III) in which R₁ is a nitro group may also be used toprepare the compounds (III) in which R₁ is a hydroxyl group by reactionwith hydroxylamine. The pyridylnitramines (R₁ =NO₂) are preparedaccording to J. Am. Chem. Soc., 1955, 77, 3154-3155.

The compounds according to the invention increase the polarization ofthe smooth muscle fibers and have a vasodilator effect on the portalvein according to the assays described in the European patentapplication 296 975. Their antihypertensive effect was observed inanimals.

Furthermore, it has been observed that the compounds according to theinvention accelerate the repolarization of the myocardial cells; at thesame time, their antiarrhythmic effect has been observed in an animalmodel.

No sign of toxicity is observed with these compounds atpharmacologically active doses.

Thus, the compounds according to the invention may be used in thetreatment of hypertension, pathological disorders associated with thecontraction of the smooth muscle fibers of the gastrointestinal,respiratory, uterine and urinary apparatuses, for example: ulcers,asthma, premature uterine contraction, incontinence, and in thetreatment of other cardiovascular diseases such as: angina pectoris,cardiac insufficiency, cerebral and peripheral vascular diseases. Inaddition, the compounds according to the invention may be used in thetreatment of cardiac arrhythmia as well as in the treatment of glaucoma.Moreover, the compounds according to the invention may be used in thetreatment of depression or other diseases of the central nervous system,such as epilepsy.

Finally, the compounds of the present invention may be used for thetopical treatment of alopecia.

Thus, another object of the present invention is pharmaceuticalcompositions containing an effective dose of one compound according tothe invention and suitable excipients. The said excipients are selectedaccording to the pharmaceutical form and the mode of administrationdesired.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical,transdermal or rectal administration, the active ingredients of formula(I) above, may be administered in dosage unit forms of administrationmixed with standard pharmaceutical vehicles to animals or humans for theprophylaxis or treatment of the above disorders and diseases. Suitablespecific forms of administration include the forms for the oral routesuch as tablets, capsules, powders, granules and oral solutions orsuspensions, buccal and sublingual forms of administration,subcutaneous, intramuscular or intravenous forms of administration andrectal forms of administration. For topical application, the compoundsaccording to the invention may be used in creams, ointments or lotions.

In order to produce the desired prophylactic or therapeutic effect, thedose of the active ingredient may be varied between 0.01 and 1 mg per kgof body weight and per day.

Each unit dose may contain from 0.01 to 2 mg, and preferably from 0.02to 1 mg of active ingredients in combination with a pharmaceuticalvehicle. This unit dose may be administered 1 to 5 times per day so asto provide a daily dose of from 0.01 to 10 mg, and preferably from 0.22to 5 mg.

When a solid composition is prepared in the form of tablets, theprincipal active ingredient is mixed with a pharmaceutical vehicle suchas gelatin, starch, lactose, magnesium stearate, talc, gum arabic orsimilar substances, the tablets may be coated with sucrose, a cellulosederivative, or other suitable materials or they may even be treated sothat they have a sustained or delayed activity and continuously releasea predetermined amount of active ingredient.

A preparation in capsular form is produced by mixing the activeingredient with a diluent and pouring the mixture obtained into soft orhard capsules.

A preparation in the form of a syrup or an elixir or for administrationin the form of drops may contain the active ingredient together with asweetener, preferably calorie-free, methylparaben and propylparaben asantiseptics, as well as an agent conferring taste and a suitablecolouring matter.

The powders or granules dispersible in water may contain the activeingredient mixed with dispersing agents or wetting agents or suspendingagents such as polyvinylpyrrolidone as well as with sweeteners or tastemodifiers.

In the case of rectal administration, suppositories are used which areprepared with binders melting at the rectal temperature, for examplecocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic salinesolutions or sterile and injectable solutions which containpharmacologically compatible wetting and/or dispersing agents, forexample propylene glycol or butylene glycol, are used.

The active ingredient may also be formulated in the form ofmicrocapsules, optionally with or without one or more additives orsupports.

The compositions of the present invention may contain, in addition tothe products of formula I above, or one of their pharmaceuticallyacceptable salts, other active ingredients such as, for example,tranquilisers, beta-blockers or other medicines which may be useful inthe treatment of the disorders or diseases indicated above.

The following examples illustrate the invention without in any waylimiting it. In the examples as well as in the descriptive part and inthe claims, some products are designated as derivatives of chroman. Itis understood that said products of the present invention arederivatives of 2,2-dimethyl 3,4-dihydro 2H-chromene and that the term"chroman" designates "3,4-dihydro 2H-chromene".

The melting points (Mp) are given in degrees centrigrade.

EXAMPLE 1 Trans 4-(2-cyanimino 1,2-dihydro 1-pyridyl) 6-cyano2,2-dimethyl 3-hydroxy chroman: SR 47023 (A+B=--CH═CH--CH═CH--; X=C--CN;R₁ =CN; R₂ =H; R₃ =OH)

2-cyanamino pyridine is prepared according to the method described inAnn. Pharm. Fr., 1968, 26 (6), 469-472.

A solution containing 1 g of 6-cyano 2,2-dimethyl 4,4-epoxy chroman, 0.8g of 2-cyanamino pyridine in 50 ml of dimethoxyethane and 0.2 ml ofbenzyltrimethylammonium hydroxide is heated at reflux for 24 hours. Thereaction mixture is concentrated, and the residue is taken up in 50 mlof water and extracted twice with ethyl acetate. The extracts are driedover sodium sulfate and concentrated. The residue is taken up in ethylether, filtered off and washed with dichloromethane. 110 mg of theexpected product are obtained.

Mp=284° C.

EXAMPLE 2 Trans 4-(2-cyanimino 1,2-dihydro 1-pyridyl) 2,2-dimethyl3-hydroxy 6-nitro chroman: SR 47025 (A+B=--CH═CH--CH═CH--; X=C--NO₂ ; R₁=CN; R₂ =H; R₃ =OH)

A solution containing 2.7 g of 2-cyanamino pyridine, 3 g of 2,2-dimethyl3,4-epoxy 6-nitro chroman in 50 ml of tetrahydrofuran and 0.2 ml oftriethylamine is heated at reflux for 96 hours. The mixture is allowedto cool and is then filtered. The precipitate is washed with ethylether, followed by water and acetone and dried, 250 mg of the expectedproduct are obtained.

Mp=253° C.

EXAMPLE 3 4-(2-cyanimino 1,2-dihydro 1-pyridyl) 2,2-dimethyl 6-nitrochromene: SR 47063 (A+B=--CH═CH--CH═CH--; X=C--NO₂ ; R₁ =CN; R₂ ++R₃=double bond)

This compound is prepared starting from the chromanol obtained inexample 2.

30 mg of sodium hydride are added in small portions to 400 mg of SR47025 placed in 50 ml of tetrahydrofuran. After 96 hours at roomtemperature, the reaction mixture is concentrated to dryness and theresidue is taken up in 50 ml of water. It is extracted twice withmethylene chloride, then the extracts are dried and evaporated todryness. 250 mg of product are obtained which are purified bychromatography on a column of silica using a methylene chloride-methanol(99.5/0.5-v/v) mixture as eluant.

80 mg of the expected product are recovered.

Mp=257° C.

EXAMPLE 4 Trans 3-acetyloxy 4-(2-cyanimino 1,2-dihydro 1-pyridyl)2,2-dimethyl 6-nitro chroman: SR 47601 (A+B=--CH═CH--CH═CH--; X=C--NO₂ ;R₁ =CN; R₂ =H; R₃ =OCOCH₃)

5 g of SR 47025, obtained in example 2 are mixed with 25 ml of pyridine,3.8 ml of acetic anhydride are added and the mixture is stirred at roomtemperature for 4 hours. The mixture is taken up in ethyl acetate, thenwashed with acidified water and dilute bicarbonate solution. The productwhich precipitates is filtered off, washed with ethyl ether then driedat 100° C. in a vacuum. 5.2 g of the expected product are obtained.

Mp=232° C.

EXAMPLE 5 4-(2-cyanimino 1,2-dihydro 1-pyridyl) 2,2-dimethyl 6-nitrochromene: SR 47063 (idem. ex. 3)

A mixture containing 5 g of SR 47061, obtained in example 4, in 100 mlof toluene is heated at reflux for 3 hours in the presence of 2.8 ml ofdiazabicycloundecene. The reaction mixture is filtered at roomtemperature and the product obtained is washed with toluene and ethylether. The product obtained (4.1 g) is recrystallized from 200 ml ofalcohol and 3 g of the expected product are obtained.

Mp=257° C.

EXAMPLE 6 Trans 6-acetyl 4-(2-cyanimino 1,2-dihydro 1-pyrimidyl)2,2-dimethyl 3-hydroxy chroman: SR 47141 (A+B=--CH═CH--CH═N--; X=--COCH₃; R₁ =CN; R₂ =H; R₃ =OH)

2-cyanamino pyrimidine is prepared according to the British patent 860423.

SR 47141 is obtained according to the method described in example 1.

Mp=254° C.

EXAMPLE 7 Trans 4-(2-cyanimino 1,2-dihydro 1-pyrimidyl) 2,2-dimethyl3-hydroxy 6-nitro chroman; SR 47162 (A+B=--CH═CH--CH═N--; X=C--NO₂ ; R₁=CN; R₂ =H; R₃ =OH)

This compound is prepared according to the procedure described inexample 6.

Mp=316° C.

EXAMPLE 8 Trans 4-(2-cyanimino 1,2-dihydro 1-pyridyl) 2,2-dimethyl3-hydroxy 6-trifluoroacetyl chroman: SR 47140 (A+B=--CH═CH--CH═CH--;X=COCF₃ ; R₁ =CN; R₂ =H; R₃ =OH)

This compound is prepared according to the method described in example1.

Mp=218° C.

EXAMPLE 9 Trans 6-cyano 4-(1,2-dihydro 2-nitrimino 1-pyridyl)2,2-dimethyl 3-hydroxy chroman: SR 47159 (A+B=--CH═CH--CH═CH--; X=C--CN;R₁ =NO₂ ; R₂ =H; R₃ =OH)

The pyridylnitramine is prepared according to the method described in J.Am. Chem. Soc., 1955, 77, 3154.

The compound of example 9 is obtained by following the procedure ofexample 2.

Mp=279° C.

EXAMPLE 10 Trans 4-(2-cyanimino 1,2-dihydro 1-pyridyl) 3,4-dihydro2,2-dimethyl 3-hydroxy pyrano [3,2-c] pyridine: SR 47142(A+B=--CH═CH--CH ═CH--; X=N; R₁ =CN; R₂ =H; R₃ =OH)

This compound is obtained starting from the epoxide (II) in which X=Nand 2-cyanamino pyridine.

Mp=171° C.

EXAMPLE 11 4-(2-cyanimino 1,2-dihydro 1-pyridyl) 2,2-dimethyl pyrano[3,2-c] pyridine: SR 47320 (A+B=--CH═CH--CH═CH--; X=N; R₁ =CN; R₂ +R₃=double bond)

A mixture of SR 47142, prepared in the previous example, 0.6 g oftetrahydrofuran and 50 mg of sodium hydride is maintained at reflux for5 hours. The reaction mixture is concentrated, taken up in water,washed, dried and concentrated to give 0.45 g of a yellow solid.Chromatography on silica is then performed using a methylenechloride-methanol mixture (99/1, v/v) as eluant. 90 mg of the expectedproduct are recovered.

Mp=256° C.

EXAMPLE 12 4-(2-cyanimino 1,2-dihydro 1-pyridyl) 6-cyano 2,2-dimethylchromene: SR 47164 (A+B=--CH═CH--CH═CH--; X=C--CN; R₁ =CN; R₂ +R₃=double bond)

A) Trans 4-(2cyanimino 1,2-dihydro 1-pyridyl) 6-cyano 2,2-dimethyl3-hydroxy chroman: prepared as in example 1.

B) SR 47164

80 mg of sodium hydride are added in small portions to 1 g of thepreviously prepared chromanol placed in 50 ml of anhydroustetrahydrofuran. After 2 hours at reflux, the reaction mixture isevaporated to dryness and the residue is taken up in 100 ml of water. Itis extracted twice with methylene chloride, then the extracts are driedand evaporated to dryness. 600 mg of product are obtained which arepurified by chromatography on a column of silica using a methylenechloride-methanol mixture (99.5/0.5 - v/v) as eluant.

400 mg of the expected product are recovered.

Mp=292° C.

EXAMPLE 13 Trans 2,2-dimethyl 3-hydroxy 4-(2-methanesulfonimino1,2-dihydro 1-pyridyl) 6-nitro chroman: SR 47195 (A+B=--CH═CH--CH═CH--;X=C--NO₂ ; R₁ =CH₃ --SO₂ --; R₂ =H; R₃ =OH)

A solution of 4.7 g of 2-amino pyridine in 6.3 ml of pyridine is cooledto 0° C. and 5.75 g of methyl chloride are added dropwise. The reactionmixture is stirred for 1 hour at 0° C., then for 24 hours at roomtemperature. The solidified reaction mixture is poured into 20 ml ofwater and stirred in order to break up the precipitate. After beingfiltered off, the solid product recovered is recrystallized from water.6.7 g of 2-methanesulfonimino pyridine are obtained.

Mp=204° C.

The usual procedure involving reaction of the product obtained with2,2-dimethyl 3,4-epoxy 6-nitro chroman is then employed in order toobtain the expected product.

Mp=265°-267° C.

EXAMPLE 14 Trans 2,2-dimethyl 3-hydroxy 4-(1,2-dihydro 2-nitrimino1-pyridyl) 6-nitro chroman; SR 47174 (A+B=--CH═CH--CH═CH--; X=NO₂ ; R₁=NO₂ ; R₂ =H; R₃ =OH)

The compound is prepared as in example 9.

EXAMPLE 15 Trans 4-(1,2-dihydro 2-methylimino 1-pyridyl) 2,2-dimethyl3-hydroxy 6-nitro chroman: SR 47220 (A+B=--CH═CH--CH═CH--; X=C--NO₂ ; R₁=CH₃ ; R₂ =H; R₃ =OH)

500 mg of SR 47174, prepared in the previous example and 50 ml ofmethylamine are mixed in a 30% ethanol solution and left at roomtemperature for 3 days. The insoluble material is filtered off, thesolvents are evaporated, the residue is taken up in ethyl ether, theprecipitate is dissolved and the insoluble material is filtered off. Theethereal phase is washed with water and dried over sodium sulfate. Theresidue is taken up in hot isopropyl ether, then the expected productcrystallizes.

m=60 mg

Mp=155° C.

EXAMPLE 16 Trans 4-[1,2-dihydro 2-(2-trifluoromethyl phenyl) sulfonimino1-pyridyl] 2,2-dimethyl 3-hydroxy 6-nitro chroman: SR 47281 (A+B=##STR7##

0.94 g of 2-amino pyridine in 5 ml of pyridine are cooled to 0° C., 2.5g of 2-trifluoromethyl phenylsulfonyl chloride are added and the mixtureis stirred overnight at room temperature. The reaction mixture is pouredinto water and extracted with methylene chloride. The organic phase iswashed with water, then dried over sodium sulfate and evaporated todryness in a vacuum. The solid residue is taken up in ethyl acetate andfiltered. 2 g of 2-(2-trifluoromethyl phenyl) sulfonimino pyridine areobtained in the form of a white solid.

Mp=218°-220° C.

SR 47281 is then prepared by reaction with 2,2-dimethyl 3,4-epoxy6-nitro chroman according to the method described in the previousexamples.

Mp=305° C.

EXAMPLES 17 TO 35

Other compounds according to the invention were prepared by using theprocedure described in the previous examples. These compounds arepresented in the tables 1 and 2 below.

                  TABLE 1                                                         ______________________________________                                         ##STR8##                      (I)                                            SR No.                                   M.p.                                 Example No.                                                                            Z        R.sub.1 R.sub.4, R.sub.5                                                                     R.sub.3 °C.                           ______________________________________                                        47163    NO.sub.2 H       H, H   OH      184                                  17                                                                            47219    CN       CF.sub.3                                                                              H, H   OH      233                                  18                                                                            47282    CN       CN      Cl, H  OH      314                                  19                                                                            47283    CN       CN      H, CH.sub.3                                                                          OH      268                                  20                                                                            47321    CN       OCH.sub.3                                                                             NO.sub.2, H                                                                          OH      164                                  21                                                                            47416    NO.sub.2 CN      H, CH.sub.3                                                                          OH      292                                  22                                                                            47417    CN       CN      CH.sub.3, H                                                                          OH      309                                  23                                                                            47433    NO.sub.2 OH      H, H   OH      219                                  24                                                                            47599    NO.sub.2 NO.sub.2                                                                              H, H   OCOCH.sub.3                                                                           237                                  25                                                                            47601    NO.sub.2 CN      H, H   OCOCH.sub.3                                                                           235                                  26                                                                            47602    COCF.sub.3                                                                             CN      H, H   OCOCH.sub.3                                                                           125                                  27                                                                            47603    Br       CN      H, H   OH      277                                  28                                                                            47604    Br       CN      H, H   OCOCH.sub.3                                                                           217                                  29                                                                            47605    CH.sub.3 CN      H, H   OCOCH.sub.3                                                                           218                                  30                                                                            ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR9##                                                                     SR No.                                                                        Example No.   Z          R.sub.1                                                                              M.p. °C.                               ______________________________________                                        47319         CN         CN     252                                           31                                                                            47600         NO.sub.2   NO.sub.2                                                                             237                                           32                                                                            47617         COCF.sub.3 CN     190                                           33                                                                            47618         Br         CN     250                                           34                                                                            48259         NH.sub.2   CN     266                                           35                                                                            ______________________________________                                    

We claim:
 1. A compound of formula (I): ##STR10## in which: A and B arelinked together between N and C═NR₁ and represent --CH═CH--CH═N--;Xrepresents a C--Z group, wherein Z represents a hydrogen, halogen, C₁-C₄ alkyl, cyano, nitro, acetyl or trifluoroacetyl, phosphono ordialkoxyphosphoryl, the alkyl group being a C₁ -C₄ group or an aminogroup; R₁ represents hydrogen, cyano, nitro, C₁ -C₄ alkyl, hydroxyl, C₁-C₄ alkoxy, trifluoroacetyl, methanesulfonyl, benzenesulfonyl,benzenesulfonyl unsubstituted or substituted on the phenyl by methyl,halogen or trifluoromethyl; R₂ represents hydrogen; and R₃ representshydroxyl or acetyloxy or R₂ and R₃ together form a bond.
 2. Apharmaceutical composition having an antihypertensive and/orantiarrhythmic effect which comprises an effective amount of onecompound of formula (I) according to claim 1 in admixture with apharmaceutically acceptable excipient.
 3. A pharmaceutical compositionaccording to claim 2 wherein the effective amount is 0.01 to 2 mg ofactive ingredient per dosage unit.
 4. A method of treating a human oranimal subject suffering from hypertension or arrhythmia comprisingadministering a pharmaceutically effective amount of a compoundaccording to claim 2 to the human or animal subject.
 5. A methodaccording to claim 4, wherein the compound is administered orally,buccally, sublingually, subcutaneously, intramuscularly, intravenouslyor rectally.
 6. A method according to claim 5, wherein the effectiveamount is 0.01 to 2 mg per kg of body weight administered 1 to 5 timesper day.